The efficacy for the pharmacological treatment of nicotine dependence has been established for nicotine replacement therapies, bupropion and most recently, varenicline. The vast majority of research in the pharmacological treatment of nicotine dependence has focused on the evaluation of single medications in placebo controlled trials, which by definition represents a one-size fits all approach to the application of the treatment. While this is appropriate in the initial stages of treatment evaluation, the potential for combined treatments to raise the level of efficacy above individual treatments alone is often unexplored. The focus of this application is on the evaluation of the combined effects of varenicline and bupropion, both in their own right FDA approved medications for smoking cessation. Both have shown effectiveness in randomized clinical trials for smoking cessation and the treatment of nicotine withdrawal symptoms. Bupropion is an atypical antidepressant whose properties include inhibition of norepinephrine re-uptake, modest dopamine re-uptake inhibition and nicotine antagonist affects. Varenicline acts primarily as a partial agonist of the 1422 nicotine cholinergic receptor in the VTA and provides an attenuated release of dopamine in the nucleus accumbens, relative to nicotine. The results from the pivotal trials of varenicline showed it to be more effective than bupropion alone. However, there are several lines of reasoning to suggest that the combination of these drugs might be more effective than varenicline alone. Plausible differences in the mechanisms of action of the two drugs and differences in their intensity of action suggest that combining these medications, will affect a broader range of the biological targets among those identified as being important for smoking cessation, and in particular may effect and enhanced response in the dopaminergic pathways The present study is a randomized, double-blinded clinical trial designed to evaluate the efficacy of varenicline, varenicline plus bupropion and placebo on smoking cessation, nicotine withdrawal, negative affect, craving, and smoking satisfaction. We will also evaluate the relationship between treatment outcomes and measures of cognitive performance. We hypothesize that smokers treated with the combination of the two medications will be abstinent significantly more often, will take a longer time to relapse, and will report significantly lower levels of nicotine withdrawal symptoms, negative affect, craving and smoking reinforcement, than those treated with varenicline alone. Continuing to develop combination therapies that target multiple biological systems will improve the chances of success on any one individual smoking cessation attempt and has the potential to inform future research on tailoring treatments to particular characteristics of the individual (i.e. comorbid history, genetics, etc). PUBLIC HEALTH RELEVANCE: This study will test the effectiveness of combining two medications, varenicline and bupropion for smoking cessation. We will also evaluate how effective this combination is for the treatment of deleterious mood and cognitive changes thought to affect success at quitting smoking. This study is important because it is unlikely that any one approach to quitting will work for all smokers and by continuing to develop new treatments that reach a broader range of smokers we can have a favorable impact on public health.